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Title:
PHOSPHATE BINDING POLYMERS
Document Type and Number:
WIPO Patent Application WO/2009/122400
Kind Code:
A1
Abstract:
Novel polymeric compounds, having a plurality of cyclic guanidine groups, processes of preparing same and uses thereof in the treatment of conditions associated with elevated serum phosphate are disclosed.

Inventors:
WULFF, Guenter (Mommsenstrasse 20, Erkrath, D-40699, DE)
GREEN, Bernard S. (38 Haim Sireni Street, Apt. 5, Rechovot, 76229, IL)
Application Number:
IL2009/000340
Publication Date:
October 08, 2009
Filing Date:
March 25, 2009
Export Citation:
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Assignee:
SEMOREX INC. (11 Byron Lane, Fanwood, New Jersey, 07023, US)
WULFF, Guenter (Mommsenstrasse 20, Erkrath, D-40699, DE)
GREEN, Bernard S. (38 Haim Sireni Street, Apt. 5, Rechovot, 76229, IL)
International Classes:
C08F8/30; A61K31/00; A61P13/12; C08F12/26; C08F20/60; C08F26/00; C08G73/02; C08J3/24
Foreign References:
US6294163B1
US20070072802A1
US20060171916A1
Other References:
GELBARD G ET AL: "Polynitrogen strong bases as immobilized catalysts" REACTIVE & FUNCTIONAL POLYMERS, ELSEVIER SCIENCE PUBLISHERS BV, NL, vol. 48, no. 1-3, 2 May 2001 (2001-05-02), pages 65-74, XP004242138 ISSN: 1381-5148
Attorney, Agent or Firm:
G.E. EHRLICH (1995) LTD. et al. (11 Menachem Begin Street, Ramat Gan, 52521, IL)
Download PDF:
Claims:

WHAT IS CLAIMED IS:

1. A polymeric compound comprising a polymeric backbone and a plurality of pendant groups attached to said polymeric backbone, wherein at least a portion of said pendant groups comprise a cyclic guanidine group.

2. The polymeric compound of claim 1, wherein said portion of said pendant groups which comprise said cyclic guanidine group is in a range of from 1 % to 100 % of said pendant groups.

3. The polymeric compound of claim 1, wherein said portion of said pendant groups which comprise said cyclic guanidine group is in a range of from 50 % to 95 % of said pendant groups.

4. The polymeric compound of any of claims 1 to 3, wherein said cyclic guanidine group is selected from the group consisting of a 5-membered and a 6- membered cyclic guanidine group.

5. The polymeric compound of claim 4, wherein said cyclic guanidine group is a 5-membered cyclic guanidine group.

6. The polymeric compound of claim 5, wherein said 5-membered cyclic guanidine group is selected from the group consisting of a 4,5-dihydroimidazol-2-amine, an alkyl-4,5-dihydroimidazol-2-amine and an alkoxy-4,5-dihydroimidazol-2-amine.

7. The polymeric compound of claim 5, wherein said 5-membered cyclic guanidine group is a 4,5-dihydroimidazol-2-amine.

8. The polymeric compound of any of claims 1-7, wherein each of said pendant groups which comprise said cyclic guanidine group independently has the general formula I:

Formula I

wherein: the curved line defines said pendant group attached to said polymeric backbone;

R 1 -R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic;

A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1 to 4 carbon atoms; and

B is absent or a linking group which links said pendant group to said polymeric backbone.

9. The polymeric compound of claim 8, wherein B is selected from the group consisting of — O-, -S-, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, alkylaryl, alkoxy, aryloxy, alkoxyalkyl, alkoxyaryl, thioalkoxy, thioaryloxy, thioalkoxyalkyl, thioalkoxyaryl, sulfinyl, alkylsulfϊnyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamide, alkylsulfonamido, amino and alkylamino.

10. The polymeric compound of claim 9, wherein B is selected from the group consisting of CH 2 , -C 6 H 4 -CH 2 -, -C(=O)-NH-CH 2 CH 2 and -C(=O)-O-CH 2 CH 2 -.

11. The polymeric compound of any of claims 1-7, wherein said polymeric backbone comprises a plurality of nitrogen atoms dispersed therewithin and each of said

pendant groups which comprise said cyclic guanidine group independently has the general formula II:

Formula II

wherein: the curved line defines said pendant group attached to said polymeric backbone;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic;

A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1 to 4 carbon atoms; and said pendant group is attached to a nitrogen atom of said polymeric backbone.

12. The polymeric compound of claim 11, wherein said polymeric backbone comprises poly(ethyleneimine) or a copolymer thereof.

13. The polymeric compound of any of claims 1-7, being derived from a polymer comprising a plurality of amine groups, said polymer being selected from the group consisting of a poly(vinylamine), a poly(4-vinylbenzylamine), a poly(allylamine), a poly(ethyleneimine), a poly(aminoethyl acrylate), a poly(aminoethyl methacrylamide), a poly(vicinalamine), and copolymers thereof, wherein at least a portion of the amine groups of said polymer comprising said plurality of amine groups are replaced by said cyclic guanidine group.

14. The polymeric compound of claim 13, wherein said polymer comprising said plurality of amine groups is a poly(allylamine).

15. The polymeric compound of any of claims 1-14, wherein a weight percentage of said cyclic guanidine groups is in a range of from 1 weight percent to 90 weight percents of a total weight of said polymeric compound.

16. The polymeric compound of claim 15, wherein a weight percentage of said cyclic guanidine groups is in a range of from 10 weight percents to 90 weight percents of a total weight of said polymeric compound.

17. The polymeric compound of any of claims 1-16, being a cross-linked polymer.

18. The polymeric compound of claim 17, being cross-linked by a cross- linking agent.

19. The polymeric compound of claim 17, being a molecularly imprinted polymer (MIP).

20. The polymeric compound of claim 19, wherein said MIP is designed capable of selectively binding a phosphate.

21. The polymeric compound of any of claims 17-20, being non-absorbable in a physiological medium.

22. The polymeric compound of any of claims 18-20, wherein said cross- linking agent is selected from the group consisting of a diacrylate, a dimethacrylate, a diacrylamide, a dimethacrylamide, epichlorohydrin, epibromohydrin, a diisocyanate, divinyl benzene, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3- dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, and pyromellitic dianhydride.

23. The polymeric compound of claim 22, wherein said cross-linking agent is epichlorohydrin.

24. A method of removing a phosphate ion from the gastrointestinal tract, the method comprising administering to a subject in need thereof a therapeutically effective amount of the polymeric compound of any of claims 1-22.

25. A use of the polymeric compound of any of claims 1-22 in the manufacture of a medicament for removing a phosphate ion from the gastrointestinal tract.

26. A method of treating or preventing a medical condition associated with an elevated serum phosphate, the method comprising administering to a subject in need thereof a therapeutically effective amount of the polymeric compound of any of claims 1-22.

27. A use of the polymeric compound of any of claims 1-22 in the manufacture of a medicament for treating or preventing a medical condition associated with an elevated serum phosphate.

28. The method of any of claims 26-27, wherein said medical condition is selected from the group consisting of hyperphosphatemia, end stage renal disease, renal insufficiency, depresses renal synthesis of calcitriol, tentany due to hypocalcemia, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, overmedication with phosphate salts, and acute tissue destruction during rhabdomyolysis and treatment of malignancies.

29. A pharmaceutical composition comprising the polymeric compound of any of claims 1-22, and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, being formulated as a liquid formulation, a tablet, a capsule, a powder, granules, a suspension, a sachet, a pill and a caplet.

31. A process of preparing the polymeric compound of any of claims 1-23, the process comprising: reacting a polymer having said polymeric backbone and comprising amino groups dispersed within said polymeric backbone and/or within a plurality of pendant groups attached to said polymeric backbone, with a cyclic guanyl compound, to thereby obtain said polymeric backbone having a plurality of pendant groups attached to said polymeric backbone, wherein at least a portion of said pendant groups comprise a cyclic guanidine group, thereby obtaining the polymeric compound.

32. The process of claim 31, wherein said cyclic guanyl compound is selected from the group consisting of a cyclic guanyl sulfonate and a methyl cyclic guanyl sulfide.

33. The process of any of claims 31-32, wherein said polymer comprising said amino groups is selected from the group consisting of a poly(vinylamine), a poly(4- vinylbenzylatnine), a poly(allylamine), a poly(ethyleneimine), a poly(aminoethyl acrylate), a poly(aminoethyl methacrylamide), a poly(vicinalamine) and a copolymer thereof.

34. The process of claim 33, wherein said polymer comprising said amino groups is a poly(allylamine).

35. A process of preparing the polymeric compound according to any of claims 1-23, the process comprising: preparing a compound having a polymerizable unit and said cyclic guanidine group being attached to said polymerizable unit; and polymerizing said compound, to thereby obtain said polymeric backbone having said plurality of pendant groups attached to said polymeric backbone, wherein at least a

portion of said pendant groups comprise a cyclic guanidine group, thereby obtaining the polymeric compound.

36. The process of claim 35, wherein said compound further comprises a linker linking said cyclic guanidine group and said polymerizable unit.

37. The process of any of claims 31-36, wherein said polymeric compound is a cross-linked polymer, the process further comprising: reacting said polymeric backbone having a plurality of cyclic guanidine moieties attached thereto with a cross-linking agent.

38. The process of any of claims 31-37, wherein said polymeric compound is a MIP, the process further comprising: reacting said polymeric backbone having a plurality of cyclic guanidine moieties attached thereto with a cross-linking agent in the presence of a phosphate.

39. The process of any of claims 37 and 38, wherein said cross-linking agent is selected from the group consisting of a diacrylate, a dimethacrylate, a diacrylamide, a dimethacrylamide, epichlorohydrin, epibromohydrin, a diisocyanate, divinyl benzene, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2- dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, and pyromellitic dianhydride.

40. The process of claim 39, wherein said cross-linking agent is epichlorohydrin.

Description:

PHOSPHATE BINDING POLYMERS

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to novel phosphate binding polymers, to processes of preparing same, and to use thereof in the treatment of conditions associated with elevated serum phosphate, such as, for example, renal diseases.

Loss of renal function leads to the accumulation of phosphates that are absorbed from the diet, leading to hyperphosphatemia and contributing to morbidity and mortality in end stage renal disease (ESRD) patients. People consuming an average US diet ingest about 7 grams/week of phosphate. The thrice weekly dialysis treatment that

ESRD patients undergo removes about 2.4 grams of phosphate. Thus, it is necessary to remove about 4.6 grams of phosphate per week from the GI tract in these patients [1, 2].

The steady increase in the incidence of ESRD and its associated morbidity and mortality is an urgent worldwide public health problem. The United States Renal Data System estimated the number of US patients with ESRD in the year 2000 to be over 300,000 [3], and the number of patients in the US is projected to be 650,000 by 2010, with expectations of growth to millions of patients by 2030. The accompanying Medicare expenditures associated with these numbers are expected to be $28 billion in 2010 [4-6]. The average global prevalence of treated ESRD was 240 patients per million population[7]. Worldwide, the highest prevalence was reported in Japan followed by Taiwan and the USA. In these countries prevalence rates were more than 1400 per million population., for treated ESRD. Portugal and Italy reported the highest prevalence rates within Europe (733 patients per million). Notably, the average prevalence for treated ESRD in Europe was lower than that in the USA and Japan. The accepted medical approach for removing the excess phosphate from ESRD patients is to take daily doses of tablets containing phosphate-binding substances, which form insoluble compounds with the phosphate ions and remove them from the body.

Metal-based substances were the first phosphate binders to be used for this purpose [1, 2]. Aluminum-based phosphate binders were used initially and were very cost effective, but their use has largely been discontinued because of the poisoning associated with their use [1, 2].

Calcium-based binders (e.g., calcium acetate or calcium carbonate, such as the drug Phoslo) are inexpensive and commonly used. However, due to their low affinity

for phosphate, large daily dosages are required (up to 20 grams/day) [1, 2]. Calcium- based binders tend to result in hypercalcemia in many patients, which leads to fatigue, muscle weakness, anorexia, nausea, constipation and vascular calcification. Thus, treatment with calcium binders is often discontinued when calcium levels rise. Another approach utilizes the lanthanum-based binder, Fosrenol, recently approved by the FDA as a phosphate binder. The use of this drug has been low due to concerns about accumulation in tissues (liver and bone) and its potential long term adverse effects.

Other efforts at developing improved metal-based binders include the polynuclear iron (III) starch/saccharose complex developed by SeBo GmbH of Germany, which selectively binds phosphate ions via chelation [8]. Alpharen is a non- aluminum, mixed metal hydroxyl carbonate compound consisting of iron and magnesium, developed by Ineos Healthcare Ltd. of United Kingdom [9]. It appears to have a higher phosphate binding capacity than other metal-containing binders. Again, the extent and the impact of systemic absorption on long term safety and/or adverse effects of these developments have not yet been evaluated for this substance.

An alternative to calcium- and metal-based binders is sevelamer hydrochloride (Renagel) [10], a non-absorbable polyamine-based polymer. Positively charged ammonium groups in sevelamer hydrochloride bind negatively charged phosphate ions in the GI tract and eliminate them from the body along with the non-absorbed polymer. The enhanced safety of Renagel, a non-metal, non-absorbable drug, has led to its becoming the leading phosphate binder drug currently in use. Thus, Renagel sales in 2005 were $418 MM [11] while sales of Fosrenol (a lanthanum metal-based binder) and Phoslo (a prescription calcium acetate formulation) in 2005 were $54 MM and $14 MM, respectively [12].

However, as its phosphate binding interaction is not specific, sevelamer hydrochloride tends to bind other anions and compounds in the GI tract, which reduce its capacity for phosphate binding and increase the dosage required to achieve effective phosphate level control (7-15 grams/day). Such high dosage is inconvenient and causes GI side effects such as bloating, nausea and diarrhea, In addition, as a result of the nonselective binding, binding of other pharmaceutical compounds can occur, leading to under-medication of other drugs administered at the same time.

Other polymer-based approaches for clinical use phosphate binding that have been disclosed in the literature are described, for example, in U.S. Patent Nos. 5,496,545, 5,667,775, 6,083,495, 6,509,013, 6,858,203 and 7,014,846 and in U.S. Patent Application No. 2006/0171916 (Genzyme). The patents and patent application teach polymers having primary amine groups (particularly poly(allylamines)) for removing phosphates. The intrinsic binding interactions of the functional groups on the polymer (primary amines) with phosphate are not strong. In addition, as with sevelamer hydrochloride, these compounds are not highly selective for phosphate binding. As a result, while these polymers may represent an improvement upon the commercially available sevelamer hydrochloride, they are not likely to represent the desired enhancement in clinical results.

U.S. Patent No. 7,342,083, which teaches polyamine polymers, and U.S. Patent No. 7,335,795, which teaches cross-linked polymers and ion binding compositions, both by Symyx Pharmaceuticals, also describe polymers with primary amines. The density of these amines, however, is increased and so the capacity of the polymer for phosphate binding. However, as with other amine-based polymers (e.g., sevelamer hydrochloride), they are not designed to enhance the binding strength or selectivity for phosphate relative to other anionic compounds that may be present, and thus the effectiveness of phosphate binding in the body is expected to be limited. In an effort to enhance the selectivity and reduce the binding of non-phosphate anion compounds in the GI tract, Ross et al. [13] developed molecularly imprinted polymers (MIPs) as phosphate binders. However, the functional monomers used by Ross et al. were not particularly effective and these MIPs display phosphate uptake that is poorer than that of Renagel. This publication mentions a very large number of chemical groupings but guanidines are not included.

Whitesides at al., in, for example, U.S. Patent No. 5,667,775, describe various phosphate binding polymers for oral administration, some of which contain guanidinium groups. U.S. Patent No. 5,880,208 teaches polyethylene-based polymers having guanidinium groups attached thereto.

SUMMARY OF THE INVENTION

Currently available phosphate binders are often characterized as non-selective, and therefore require large daily dosages for effectively controlling phosphate level (up to 20 grams/day). Such a large dosage is inconvenient and causes gastrointestinal side effects. The non-selective binding can further result in binding of pharmaceuticals used by the treated patient, leading to under-medication.

In a search for a novel, non-absorbable, polymer-based drug with improved selectivity and enhanced capacity for phosphate binding, and which would thus circumvent the need to use high doses and would cause reduced GI side effects and other adverse effects (e.g., under-medication of other drugs), the present inventors have designed and successfully prepared and practiced polymeric compounds which comprise cyclic guanidine groups.

While reducing the present invention to practice, the present inventors surprisingly uncovered that the cyclic guanidine-containing polymers bind phosphate with a higher affinity than do currently available polymeric phosphate binders.

Without being bound to any particular theory, the present inventors have hypothesized that the presence of cyclic guanidine moieties enhances the selective phosphate binding of the polymers due to the distributed positive charge in cyclic guanidines and the rigidity thereof. Thus, according to an aspect of some embodiments of the present invention there is provided a polymeric compound comprising a polymeric backbone and a plurality of pendant groups attached to the polymeric backbone, wherein at least a portion of the pendant groups comprise a cyclic guanidine group.

According to an aspect of some embodiments of the present invention there is provided a method of removing a phosphate ion from the gastrointestinal tract, the method comprising administering to a subject in need thereof a therapeutically effective amount of the polymeric compound described herein.

According to an aspect of some embodiments of the present invention there is provided a use of the polymeric compound described herein in the manufacture of a medicament for removing a phosphate ion from the gastrointestinal tract.

According to an aspect of some embodiments of the present invention there is provided a method of treating or preventing a medical condition associated with an

elevated serum phosphate, the method comprising administering to a subject in need thereof a therapeutically effective amount of the polymeric compound described herein. According to an aspect of some embodiments of the present invention there is provided a use of the polymeric compound described herein in the manufacture of a medicament for treating or preventing a medical condition associated with an elevated serum phosphate.

According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition comprising the polymeric compound described herein, and a pharmaceutically acceptable carrier. According to some embodiments, the medical condition is selected from the group consisting of hyperphosphatemia, end stage renal disease, renal insufficiency, depresses renal synthesis of calcitriol, tetany due to hypocalcemia, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, overmedication with phosphate salts, and acute tissue destruction during rhabdomyolysis and treatment of malignancies.

According to some embodiments, the portion of the pendant groups which comprise the cyclic guanidine group is in a range of from 1 % to 100 % of the pendant groups.

According to some embodiments, the portion of the pendant groups which comprise the cyclic guanidine group is in a range of from 50 % to 95 % of the pendant groups.

According to some embodiments, the cyclic guanidine group is selected from the group consisting of a 5-membered and a 6-membered cyclic guanidine group.

According to some embodiments, the cyclic guanidine group is a 5-membered cyclic guanidine group.

According to some embodiments, the 5-membered cyclic guanidine group is selected from the group consisting of a 4,5-dihydroimidazol-2-arnine, an alkyl-4,5- dihydroimidazol-2-amine and an alkoxy-4,5-dihydroimidazol-2-amine.

According to some embodiments, the 5-membered cyclic guanidine group is a 4,5-dihydroimidazol-2-amine.

According to some embodiments, each of the pendant groups which comprise the cyclic guanidine group independently has the general formula I:

Formula I

wherein: the curved line defines the pendant group attached to the polymeric backbone; R 1 -R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic;

A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1 to 4 carbon atoms; and

B is absent or a linking group which links the pendant group to the polymeric backbone.

According to some embodiments, B is selected from the group consisting of — O-

, -S-, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, alkylaryl, alkoxy, aryloxy, alkoxyalkyl, alkoxy aryl, thioalkoxy, thioaryloxy, thioalkoxyalkyl, thioalkoxyaryl, sulfmyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino.

According to some embodiments, B is selected from the group consisting of CH 2 , -C 6 H 4 -CH 2 -, -C(=O)-NH-CH 2 CH 2 and -C(=O)-O-CH 2 CH 2 -.

According to some embodiments, the polymeric backbone comprises a plurality of nitrogen atoms dispersed therewithin and each of the pendant groups which comprise the cyclic guanidine group independently has the general formula II:

Formula II

wherein: the curved line defines the pendant group attached to the polymeric backbone;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic;

A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1 to 4 carbon atoms; and the pendant group is attached to a nitrogen atom of the polymeric backbone.

According to some embodiments, the polymeric backbone comprises poly(ethyleneimine) or a copolymer thereof.

According to some embodiments, the polymeric compound is derived from a polymer comprising a plurality of amine groups, the polymer being selected from the group consisting of a poly(vinylarnine), a poly(4-vinylbenzylamine), a poly(allylamine), a poly(ethyleneimine), a poly(aminoethyl acrylate), a poly(aminoethyl methacrylamide), a poly(vicinalamine), and copolymers thereof, wherein at least a portion of the amine groups of the polymer comprising the plurality of amine groups are replaced by the cyclic guanidine group. According to some embodiments, the polymer comprising the plurality of amine groups is a poly(allylamine).

According to some embodiments, a weight percentage of the cyclic guanidine groups is in a range of from 1 weight percent to 90 weight percents of a total weight of the polymeric compound. According to some embodiments, a weight percentage of the cyclic guanidine groups is in a range of from 10 weight percents to 90 weight percents of a total weight of the polymeric compound.

According to some embodiments, the polymeric compound is a cross-linked polymer.

According to some embodiments, the polymeric compound is cross-linked by a cross-linking agent. According to some embodiments, the polymeric compound is a molecularly imprinted polymer (MIP).

According to some embodiments, the MIP is designed capable of electively binding a phosphate.

According to some embodiments, the polymeric compound is non-absorbable in a physiological medium.

According to some embodiments, the pharmaceutical composition is formulated as a liquid formulation, a tablet, a capsule, a powder, granules, a suspension, a sachet, a pill and a caplet.

According to some embodiments, the process of preparing the polymeric compound comprises reacting a polymer having the polymeric backbone described herein and comprising amino groups dispersed within the polymeric backbone and/or within a plurality of pendant groups attached to the polymeric backbone, with a cyclic guanyl compound, to thereby obtain the polymeric backbone having a plurality of pendant groups attached to the polymeric backbone, wherein at least a portion of the pendant groups comprise a cyclic guanidine group, thereby obtaining the polymeric compound.

According to some embodiments, the cyclic guanyl compound is selected from the group consisting of a cyclic guanyl sulfonate and a methyl cyclic guanyl sulfide.

According to some embodiments, the polymer comprising amino groups is selected from the group consisting of a poly(vinylamine), a poly(4-vinylbenzylamine), a poly(allylamine), a poly(ethyleneimine), a poly(aminoethyl acrylate), a poly(aminoethyl methacrylamide), a poly(vicinalamine) and a copolymer thereof.

According to some embodiments, the polymer comprising amino groups is a poly(allylamine). According to some embodiments, the process of preparing the polymeric compound comprises preparing a compound having a polymerizable unit and the cyclic guanidine group described herein being attached to the polymerizable unit, and

polymerizing the compound, to thereby obtain the polymeric backbone having the plurality of pendant groups attached to the polymeric backbone, wherein at least a portion of the pendant groups comprise a cyclic guanidine group, thereby obtaining the polymeric compound. According to some embodiments, the compound further comprises a linker linking the cyclic guanidine group and the polymerizable unit.

According to some embodiments, the polymeric compound is a cross-linked polymer, and the process further comprises reacting the polymeric backbone having a plurality of cyclic guanidine moieties attached thereto with a cross-linking agent. According to some embodiments, the polymeric compound is a MIP, and the process further comprises reacting the polymeric backbone having a plurality of cyclic guanidine moieties attached thereto with a cross-linking agent in the presence of a phosphate.

According to some embodiments, the cross-linking agent is selected from the group consisting of a diacrylate, a dimethacrylate, a diacrylamide, a dimethacrylamide, epichlorohydtin, epibromohydrin, a diisocyanate, divinyl benzene, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2- dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, and pyromellitic dianhydride. According to some embodiments, the cross-linking agent is epichlorohydrin.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and

for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced. In the drawings: FIG. 1 is a scheme showing a synthetic pathway for preparing an exemplary cyclic guanidine-containing polymer according to embodiments of the invention (Compound 6) via the preparation of an exemplary cyclic guanyl compound (Compound 4), which is used to synthesize exemplary cyclic guanidine-containing polymerizable monomers (Compounds 5 and 7); FIG. 2 is a scheme showing two synthetic pathways for preparing exemplary polymeric compounds according to some embodiments of the invention (Compounds 13A and 13B) from poly(allylamine) (Compound 10);

FIG. 3 is a scheme showing the preparation of an exemplary cyclic guanidine- containing polymer according to some embodiments of the invention by reacting the commercially available drug sevelamer hydrochloride with a cyclic guanyl compound (Compound 4 or 9); and

FIG. 4 is a scheme showing the preparation of a non-substituted (linear) guanidine-containing polymerizable monomer (Compound 17) and a cyclic guanidine- containing polymerizable monomer (Compound 18) from allylamine, and the preparation of the corresponding polymers (Compounds 19 and 20, respectively).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to novel phosphate binding polymers, to processes of preparing same, and to use thereof in the treatment of conditions associated with elevated serum phosphate, such as, for example, renal diseases.

In a search for novel phosphate binding polymers, which would obviate the drawbacks associated with currently available phosphate binding polymers, the present inventors have designed and successfully prepared and practiced novel polymeric compounds which comprise cyclic guanidine-containing pendant groups, and which can be prepared in a simple and convenient manner.

The present inventors have surprisingly uncovered that these polymeric compounds are capable of binding phosphate with a high affinity, and moreover, with an

affinity superior to that of currently available phosphate binding polymers. These polymeric compounds can therefore be advantageously utilized in a variety of applications, such as, for example, binding phosphate in order to treat a variety of medical conditions that are associated with elevated levels of serum phosphate (e.g., renal diseases).

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Referring now to the drawings, FIG. 1 schematically illustrates a process for producing an exemplary polymeric compound according to some embodiments of the present invention, effected by preparing an exemplary Compound 4, which can be used to prepare a cyclic guanidine-containing polymerizable monomer (Compound 5), which in turn can be polymerized to form a polymer comprising cyclic guanidine-containing pendant groups (Compound 6).

FIGs. 2 and 3 schematically illustrate syntheses of exemplary cyclic guanidine- containing polymeric compounds from poly(allylamine).

FIG. 4 schematically illustrates the syntheses of polymers with cyclic guanidine- containing pendant groups and polymers with non-substituted, linear guanidine- containing pendant groups.

Thus, according to one aspect of embodiments of the invention there is provided a polymeric compound comprising a polymeric backbone and a plurality of pendant groups attached to the polymeric backbone, wherein at least a portion of the pendant groups comprise a cyclic guanidine group. The portion of pendant groups which comprise a cyclic guanidine group can be in a range of from 1 % to 100 % of the total number of the pendant groups attached to the polymeric backbone.

In some embodiments, the portion of pendant groups which comprise a cyclic guanidine group is greater than 20 %, greater than 30 %, greater than 40 %, and is preferably greater than 50 % of the total number of pendant groups attached to the polymeric backbone. In some embodiments, the portion of pendant groups which comprise a cyclic guanidine group is in a range of from 50 % to 95 %, from 60 % to 95

%, from 70 % to 95 %, from 80 % to 95 %, and even from 90 % to 95 %, of the total number of pendant groups attached to the polymeric backbone.

As used herein, the phrase "polymeric backbone" refers to a chain of atoms (e.g., carbon, nitrogen, oxygen and/or sulfur atoms) which form a backbone of a polymer, as well as any hydrogen atoms attached directly thereto. The polymeric backbone of the compound is on average at least 20 atoms in length, optionally at least 100 atoms in length, and optionally at least 500 atoms in length, and can also be of much higher lengths. The backbone may be linear or branched. In embodiments wherein the backbone is branched, each branch of the backbone is at least 20 atoms in length, optionally at least 100 atoms in length, and optionally at least 500 atoms in length, and can also be of much higher lengths.

As used herein, the phrase "pendant group" describes a chemical group

(excluding hydrogen) which is attached to the polymeric backbone, and which is not a part of the polymeric backbone, as defined hereinabove. As used herein, the phrase "guanidine group" describes a -NRa-C(=N + RbRc)-

NRdRe group, wherein Ra-Re are any suitable substituent(s). Non-limiting examples of suitable substituents include hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic, as these terms are defined herein.

As used herein, the phrase "cyclic guanidine", which is also referred to herein interchangeably as "cycloguanidine", describes a guanidine group as described hereinabove, wherein Rc and Re are joined together so as to form a ring.

In some embodiments, the cyclic guanidine groups described herein are collectively represented by the following general formula:

Wherein:

the curved line defines the cyclic guanidine group (whereby the bond it intersects links the cyclic guanidine to another moiety);

A is a linking group (e.g., alkylene) formed from the Rc and Re groups of a corresponding non-cyclic guanidine, and Ra, Rb and Rd are as described hereinabove. As used herein throughout, the curved line in a formula indicates the bond via which the depicted group is attached to the other parts of the polymeric compound (e.g., the polymeric backbone or a linking group linking the cyclic guanidine group and the polymeric backbone).

Guanidine groups which are not cyclic are referred to herein interchangeably as "linear guanidine groups" or "non-cyclic guanidine groups". Linear guanidine groups which are not substituted (i.e., Ra-Re are each hydrogen) are referred to herein as "non- substituted guanidine groups".

According to some embodiments, the cyclic guanidine group is a 5-membered or a 6-membered cyclic guanidine group. Thus, the A group described hereinabove provides two of the atoms of the ring (e.g., -CH 2 CH 2 -), resulting in a 5-membered ring, or A provides 3 of the atoms of the ring (e.g., -CH 2 CH 2 CH 2 -), resulting in a 6-membered ring.

The A group can be a non-saturated or a saturated group.

In some embodiments, the A group is selected such that the cyclic guanidine group contains a non-aromatic ring.

As is known in the art, the chemical properties of guanidine groups are determined to a significant degree by the conjugated pi-electron system encompassing the three nitrogen atoms of the guanidine.

Hence, in some embodiments, none of the groups attached to the nitrogen atoms in the cyclic guanidine (e.g., Ra, Rb, Rd and A) comprise an electronic structure that can significantly affect the electronic properties of the guanidine group (e.g., an electron withdrawing group, an unsaturated bond conjugated to the guanidine pi-electron system).

A non-limiting example of a cyclic guanidine group is 4,5-dihydroimidazol-2- amine, which is characterized as comprising a 4,5-dihydroimidazole (also referred to herein as imidazoline) ring, wherein, in the general formula hereinabove A is CH 2 CH 2 , and Ra, Rb and Rd are each hydrogen.

Additional, non-limiting examples of cyclic guanidine groups include alkyl-4,5- dihydroimidazol-2-amine, wherein, in the general formula hereinabove A is -CH 2 C(- alkyl)H-, and Ra, Rb and Rd are each hydrogen; alkoxy-4,5-dihydroimidazol-2-amine, wherein, in the general formula hereinabove A is -CH 2 C(-O-alkyl)H-, and Ra, Rb and Rd are each hydrogen; and l,4,5,6-tetrahydropyrimidin-2-amine, wherein, in the general formula hereinabove A is CH 2 CH 2 CH 2 , and Ra, Rb and Rd are each hydrogen. In some embodiments, the above-described alkyl and alkoxy substituents of 4,5- dihydroimidazol-2-amine comprise 1 to 4 carbon atoms, and are non-substituted.

According to some embodiments, each of the pendant groups which comprise a cyclic guanidine group has the general formula I:

Formula I

Wherein: the curved line defines the portion of the pendant group attached to the polymeric backbone (whereby the bond intersected by the curved line represents the bond linking the pendant group to the polymeric backbone);

R 1 -R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic; and

A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1-4 carbon atoms.

In exemplary compounds, A is saturated and unsubstituted. In some embodiments, each OfR 1 -R 3 are hydrogen. In some embodiments, B is absent, such that the cyclic guanidine group is attached directly to the polymeric backbone.

In some embodiments, B is a linking group which links the pendant group and the polymeric backbone. Non-limiting examples of suitable linking groups, according to some embodiments of the invention, include heteroatoms such as -O- or -S-, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, alkylaryl, alkoxy, aryloxy, alkoxyalkyl, alkoxyaryl, thioalkoxy, thioaryloxy, thioalkoxyalkyl, thioalkoxyaryl, sulfinyl, alkylsulfmyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these are defined herein.

In some embodiments, B is an alkylaryl (e.g., -C 6 H 4 -CH 2 -), alkyl (e.g., -CH 2 -), alkylamido (e.g., -C(=O)-NH-CH 2 CH 2 -) or alkylcarboxylate (e.g., -C(O)-O-CH 2 CH 2 -).

As used herein, the phrase "linking group", also referred to herein interchangeably as "linker", describes a group which attaches to a plurality of moieties (e.g., the cyclic guanidine group and the polymeric backbone), thereby linking the moieties together.

Each of the chemical groups described herein can be either a linking group, as defined herein, or an end group.

As used herein, the phrase "end group" describes a group which attaches to a single moiety.

It will be appreciated by one of skills in the art that the feasibility of each of the end groups (e.g., substituents), moieties (e.g., A in the general formulae) and linking groups to be located at the indicated positions depends on the valency, chemical stability and/or chemical compatibility of the substituent, moiety or linking group. Hence, the present invention is aimed at encompassing all the feasible options.

The linking groups described herein may be aligned in any direction (e.g., either end of the linking group may be connected to the cyclic guanidine group or the polymeric backbone).

In some embodiments, the nitrogen atom of the cyclic guanidine group which is attached to the linking group B is attached to a carbon atom, if present, in the linking group.

As discussed hereinabove, in some embodiments, none of the groups attached to the nitrogen atoms of the guanidine group comprise an electronic structure which significantly affects the guanidine group. Thus, in such embodiments, the portion of the linker which attaches to the guanidine group does not comprise an electronic structure (e.g., strong electron withdrawing groups, unsaturated bonds which are conjugated to the guanidine pi-electron system) which significantly affects the guanidine group.

Thus, in some embodiments, the carbon atom in the linking group is attached only to hydrogen or carbon atoms, in addition to the nitrogen atom of the cyclic guanidine group. Thus, for example, in such embodiments, if B is -C^O)-O-CH 2 CH 2 -, it is such that the nitrogen atom of the guanidine group is attached to a carbon of the

CH 2 CH 2 portion of the group, rather than to the C(=0)-0 portion.

It is noted that, as further discussed in detail hereinbelow, some of the polymeric compounds described herein are obtained by attaching cyclic guanidine to pendant groups of existing polymers. The B linking group in the general Formula above can therefore be composed of such pendant groups, to which the cyclic guanidine is bound directly or indirectly.

According to some embodiments, the polymeric backbone comprises a plurality of nitrogen atoms dispersed therewithin and the cyclic guanidine group shares a nitrogen atom with the polymer backbone. In such embodiments, the pendant groups which comprise a cyclic guanidine group can be collectively represented by the general formula II:

Formula II

wherein the curved line defines the portion of the pendant group attached to a nitrogen atom within the polymeric backbone, whereby the bond intersected by the curved line represents the bond linking the pendant group to the nitrogen atom within the

polymeric backbone; R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic; A is a saturated or unsaturated, substituted or unsubstituted alkylene having 1 to 4 carbon atoms; and the pendant group is attached to a nitrogen atom of the polymeric backbone. In exemplary compounds A is saturated and unsubstituted. In some embodiments, each OfR 1 -R 3 are hydrogen.

Polymeric backbones which comprise nitrogen atoms therewithin include, for example, poly(ethyleneimine).

As used herein throughout, the term "alkyl" refers to a saturated or unsaturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., "1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, disulfide, sulfmyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, cyano, nitro, azide, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, oxo, carbonyl, thiocarbonyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these terms are defined herein. As used herein, the term "alkylene" describes a linking group which is an alkyl, as these terms are defined herein, wherein the aliphatic hydrocarbon portion of the alkyl attaches to a plurality of moieties, thereby linking the moieties together.

A linking group which is a substituted or non-substituted alkyl group is also referred to herein as alkylene. In some embodiments, a linking group which is a substituted alkyl attaches to one of the moieties (polymeric backbone or cyclic guanidine) via a substituent of the alkyl.

In one example, an alkyl linking group substituted by an amino group (e.g., an aminoalkyl) is attached to the polymeric backbone via the amino group and to the cyclic guanidine via the alkyl portion.

In another example, an aikyl linking group substituted by an alkoxy group (e.g., an alkoxyalkyl) is attached to the polymeric backbone via the alkyl portion and to the cyclic guanidine via the alkoxy group.

In another example, an alkyl linking group substituted by an alkylcarboxylate group is attached to the polymeric backbone via the alkyl portion and to the cyclic guanidine via the alkyl portion of the alkylcarboxylate substituent. A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring {i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, disulfide, sulfinyl, alkylsulfmyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, cyano, nitro, azide, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, oxo, carbonyl, thiocarbonyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these terms are defined herein.

An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic {i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, disulfide, sulfϊnyl, alkylsulfmyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, cyano, nitro, azide, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, oxo, carbonyl, thiocarbonyl, urea, alkylurea, thiourea,

alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these terms are defined herein.

A "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, disulfide, sulfmyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, cyano, nitro, azide, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, oxo, carbonyl, thiocarbonyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these terms are defined herein.

A "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or unsubstituted. When substituted, the substituted group can be, for example, lone pair electrons, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, disulfide, sulfinyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, sulfonate, alkylsulfonate, sulfate, alkylsulfate, cyano, nitro, azide, phosphonyl, alkylphosphonyl, phosphinyl, alkylphosphinyl, oxo, carbonyl, thiocarbonyl, urea, alkylurea, thiourea, alkylthiourea, carbamyl, alkylcarbamyl, thiocarbamyl, alkylthiocarbamyl, amido, alkylamido, carboxylate, alkylcarboxylate, sulfonamido, alkylsulfonamido, amino and alkylamino, as these terms are defined herein. Representative examples are 4,5-dihydroimidazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine and the like.

Cycloalkyl, aryl, heteroaryl and heteroalicyclic groups may be linking groups. In some embodiments, a linking group which is a substituted cycloalkyl, aryl, heteroaryl or heteroalicyclic attaches to a plurality of moieties solely via the atoms in the rings of the cycloalkyl, aryl, heteroaryl or heteroalicyclic.

In other embodiments, a linking group which is a substituted cycloalkyl, aryl, heteroaryl or heteroalicyclic attaches to a moiety via a substituent attached to a cycloalkyl, aryl, heteroaryl or heteroalicyclic ring.

For example, an aryl linking group which is substituted by an alkyl group may be attached to the polymeric backbone via the aryl portion, and to the cyclic guanidine via the alkyl group. As used herein, the terms "amine" and "amino" refer to a — NR'R" group, wherein R' and R' ' are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, cycloalkyl, heteroalicyclic (bonded through a ring carbon), aryl, and heteroaryl (bonded through a ring carbon), wherein when the amino group is a linking group, at least one of R' and R" is absent, such that the group is, e.g., a -N(R')- group. Optionally, R' and R" are selected from the group consisting of hydrogen and alkyl comprising 1 to 4 carbon atoms. Optionally, R' and R" are each hydrogen.

An "alkylamino" group refers to both an -alkyl-amino and -cycloalkyl-amino group, as defined herein. It is to be appreciated that the alkylamino group will therefore be a linking group whenever the amino group therein is a linking group. A "hydroxy" group refers to an -OH group.

An "azide" group refers to a -N=N + =N " group.

An "alkylaryl" group refers to alkyl or cycloalkyl group attached to (or substituted by) an aryl or heteroaryl group, as defined herein. In some embodiments, the term "alkylaryl" is used in the context of a linking group to describe a linking group composed of an alkyl that attaches one moiety, and is further attached to an aryl, which in turn attaches another moiety. In some embodiments, the alkyl portion of the alkylaryl attaches to the cyclic guanidine, whereby the aryl portion attaches to the polymeric backbone.

An "alkoxy" group refers to both an -O-alkyl end group and an -O-cycloalkyl end group, as well as to -O-alkylene- and -O-cycloalkyl- linking groups, as defined herein.

An "aryloxy" group refers to both an -O-aryl end group and an -O-heteroaryl end group, as well as to -O-aryl- and -O-heteroaryl- linking groups, as defined herein.

It is to be appreciated that an alkoxy or aryloxy group is a linking group whenever the alkyl, cycloalkyl, aryl or heteroaryl group therein is a linking group. An "alkoxyalkyl" group refers to an -alkylene-O-alkylene, -alkylene-O- cycloalkyl, -cycloalkyl-O-alkylene or -cycloalkyl-O-cycloalkyl linking group, as well as to -alkyl-O-alkyl-, -alkyl-O-cycloalkyl- and -cycloalkyl-O-cycloalkyl- end groups, as defined herein.

An "alkoxyaryl" group refers to an -aryl-O-alkyl, -aryl-O-cycloalkyl, - heteroaryl-O-alkyl or -heteroaryl-O-cycloalkyl end group, as well as to -aryl-O- alkylene-, -aryl-O-cycloalkyl-, -heteroaryl-O-alkylene- or -heteroaryl-O-cycloalkyl- linking groups, as defined herein.

A "thiohydroxy" group refers to a -SH group.

A "thioalkoxy" group refers to both an -S-alkyl end group, and an -S-cycloalkyl end group, as well as to -S-alkylene- and —S-cycloalkyl- linking groups, as defined herein.

A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl end group, as well as to —S-aryl- and —S-heteroaryl- linking groups, as defined herein.

A "thioalkoxyalkyl" group refers to an -alkyl-S-alkyl, -alkyl-S-cycloalkyl, - cycloalkyl-S-alkyl or -cycloalkyl-S-cycloalkyl end group, as well as to -alkylene-S- alkylene-, -alkylene-S-cycloalkyl- or -cycloalkyl-S-cycloalkyl- linking groups, as defined herein.

A "thioalkoxyaryl" group refers to an -aryl-S-alkyl, -aryl-S-cycloalkyl, - heteroaryl-S -alkyl or -heteroaryl-S-cycloalkyl end group, as well as to an -aryl-S- alkylene-, -aryl-S-cycloalkyl-, -heteroaryl-S-alkyl- or -heteroaryl-S-cycloalkyl- linking group, as defined herein.

A "sulfide" refers to both a thioalkoxy and a thioaryloxy end group, wherein the group is linked to an alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic group.

A "disulfide" group refers to both a-S-thioalkoxy and a -S-thioaryloxy group. A "carbonyl" group refers to a -C(=O)-R' end group, where R' is defined as hereinabove, and to a -C(=O)- linking group.

A "thiocarbonyl" group refers to a -C(=S)-R' end group, where R' is as defined herein, and to a — C(=S)- linking group.

An "oxo" group refers to a =0 group.

A "carboxylate" encompasses both -C(=O)-O-R' and R'C(=O)-O- end groups, and a -C(=O)-O- linking group, as defined herein.

A carboxylate linking group can attach to the polymeric backbone via the oxygen atom and to the cyclic guanidine via the carbon atom, or vice versa.

An "alkylcarboxylate" group refers to both an -alkyl-carboxylate and - cycloalkyl-carboxylate end group, as well as to -alkylene-carboxylate- and -cycloalkyl- carboxylate- linking groups, as defined herein.

A "carboxylic acid" group refers to a -C(=O)-OH group.

A "thiocarboxy" or "thiocarboxylate" group refers to both -C(=S)-O-R' and -O- C(=S)R' end groups, as well as to a -C(=S)-O- linking group.

An alkylcarboxylate or alkylthiocarbocylate linking group can attach the cyclic guanidine group via the alkyl portion and to the polymeric backbone via the carboxylate or thiocarboxylate portion, respectively, or vice versa.

A "halo" group refers to fluorine, chlorine, bromine or iodine.

A "sulfinyl" group refers to an -S(=O)-R' end group, where R' is as defined herein, and to a -S(=O)- linking group. An "alkylsulfinyl" group refers to both an -alkyl-sulfinyl and -cycloalkyl- sulfinyl end group, as well as to an -alkylene-sulfϊnyl- or -cycloalkyl-sulfmyl- linking groups, as defined herein.

A "sulfonyl" group refers to an -S(=O) 2 -R' end group, where R' is as defined herein, and to a -S(=O) 2 - linking group. An "alkylsulfonyl" group refers to both an — alkyl-sulfonyl and -cycloalkyl- sulfonyl end group, as well as to an -alkylene-sulfonyl- or -cycloalkyl-sulfonyl- linking group, as defined herein.

A "sulfonate" group refers to an -S(=O) 2 -O-R' end group, where R' is as defined herein, and to an -S(=O) 2 -O- linking group. An "alkylsulfonate" group refers to both an -alkyl-sulfonate and -cycloalkyl- sulfonate end group, as well as to an -alkyene-sulfonate- or -cycloalkyl-sulfonate- linking group, as defined herein.

A "sulfate" group refers to an -0-S(^O) 2 -O-R' end group, where R' is as defined as herein, and to a -O-S(=O) 2 -O- linking group.

An "alkylsulfate" group refers to both an -alkyl-sulfate and -cycloalkyl-sulfate end group, as well as to an -alkylene-sulfate- or -cycloalkyl-sulfate- linking group, as defined herein.

A "sulfonamide" or "sulfonamido" group encompasses both -SO=O) 2 -NR 5 R" and R'S(=0) 2 -N(R')- end groups, and a -S(=O) 2 -N(R')- linking group, as defined herein.

An "alkylsulfonamido" group refers to both -alkyl-sulfonamido and -cycloalkyl- sulfonamido end group, as well as an -alkyl-sulfonamido- or -cycloalkyl-sulfonamido- linking group, as defined herein.

A "carbamyl" or "carbamate" group encompasses -OC(=O)-NR'R" and R'OC(-O)-NR"- end groups and a -0C(=0)-NR"- linking group.

An "alkylcarbamyl" group refers to both an — alkyl-carbamyl and -cycloalkyl- carbamyl end group, as well as to an -alkyl-carbamyl- or — cycloalkyl-carbamyl- linking group, as defined herein.

A "thiocarbamyl" or "thiocarbamate" group encompasses -OC(=S)-NR'R" and R'0C(=S)-NR"- end groups and a -OC(=S)-NR"- linking group.

An "alkylthiocarbamyl" group refers to both an — alkyl-thiocarbamyl and - cycloalkyl-thiocarbamyl end group, as well as to an —alkyl-thiocarbamyl- or — cycloalkyl-thiocarbamyl- linking group, as defined herein.

An "amide" or "amido" group encompasses -C(=0)-NR'R" and R 5 C(O)- NR"- end groups and a -C(=0)-NR"- linking group.

An "alkylamido" group refers to both -alkyl-amido and -cycloalkyl-amido end group, as well as an -alkyl-amido- or -cycloalkyl-amido- linking group, as defined herein.

A "urea" group refers to an -N(R')-C(=0)-NR"R'" end group, where each of R' and R" is as defined herein, and R'" is defined as R' and R" are defined herein, and to an-N(R')-C(=0)-NR"- linking group. An "alkylurea" group refers to both an -alkyl-urea and -cycloalkyl-urea end group, as well as to an -alkyl-urea- or -cycloalkyl-urea- linking group, as defined herein.

A "nitro" group refers to an -NO 2 group.

A "cyano" group refers to a -C≡N group.

The term "phosphonyl" or "phosphorate" describes a -P(=O)(OR')(OR") end group, with R' and R" as defined hereinabove, and a -P(=O)(OR')-O- linking group. An "alkylphosphonyl" group refers to both an -alkyl-phosphonyl and - cycloalkyl-phosphonyl end group, as well as to an —alkyl-phosphonyl- or -cycloalkyl- phosphonyl- linking group, as defined herein.

The term "phosphate" describes an -O-P(=O)(OR')(OR") end group, with each of R' and R" as defined hereinabove, and an -C>-P(=O)(OR')-O- linking group. The term "phosphinyl" describes a -PR' R" end group, with each of R' and R" as defined hereinabove, and a -PR'- linking group.

An "alkylphosphinyl" group refers to both an -alkyl-phosphinyl and - cycloalkyl-phosphinyl end group, as well as to an -alkyl-phosphinyl- or -cycloalkyl- phosphinyl- linking group, as defined herein. The term "thiourea" describes a -N(R')-C(=S)-NR"R'" end group, with each of R', R" and R'" as defined hereinabove, and to a~N(R')-C(=S)-NR"- linking group.

An "alkylthiourea" group refers to both an -alkyl-thiourea and -cycloalkyl- thiourea end group, as well as to an -alkyl-thiourea- or -cycloalkyl-thiourea linking group, as defined herein. Hereinthroughout, the pendant groups of the polymeric compounds presented herein, which comprise cyclic guanidine group are also referred to as "cyclic-guanidine containing pendant groups". The polymeric compounds described herein are also referred to as "cyclic guanidine-containing polymeric compounds" or "cyclic guanidine- containing polymers". In some embodiments, the polymeric compounds presented herein may be described as derivatives of a polymer which comprises a plurality of amine groups, wherein at least a portion of the amine groups are converted to cyclic guanidine groups. Such derivatives are described herein as "cyclic guanidine derivatives" or "cycloguanidine derivatives". Thus, a cyclic guanidine derivative of a polymer (e.g., poly(ethyleneimine)) comprising amine groups dispersed within the backbone thereof will comprise pendant groups having general formula II shown hereinabove. Cyclic guanidine derivatives of a

polymer comprising pendant groups which include, or consist of, an amine group, will comprise pendant groups having general formula I shown hereinabove.

For example, pendant groups of a cyclic guanidine derivative of poly(allylamine) will have general formula I, wherein the linking group B is CH 2 , whereas for derivatives of poly(aminoethyl acrylate) and poly(aminoethyl methacrylamide), the linking group B is -CC=O)-O-CH 2 CH 2 - or -C(^O)-NH-CH 2 CH 2 -, respectively. Pendant groups of cyclic guanidine derivatives of poly(vinylamine) have general formula I wherein B is absent.

Exemplary polymeric compounds according to some embodiments of the invention are derived from a poly(allylamine). The density of cyclic guanidine groups attached to a polymer backbone is affected, for example, by the density of amine groups on an amine-containing polymer from which the polymeric compound is derived, as well as by the percentage of amine groups which are converted to cyclic guanidine groups. Thus, amine-containing polymers formed of vinylic monomer residues (e.g., vinylamine, allylamine and aminoethyl acrylate residues) typically comprise one amine-containing pendant group for each two backbone carbon atoms, such that cyclic guanidine derivatives thereof will exhibit a ratio of at most about 0.5 cyclic guanidine groups per atom of the backbone.

A higher density of cyclic guanidine groups may be obtained with cyclic guanidine derivatives of polymers comprising vicinal amines (i.e. amine-containing pendant groups attached to adjacent atoms of the backbone). Such polymers are referred to herein as a "poly(vicinalamine)". Cyclic guanidine derivatives of poly(vicinalamines) may exhibit a ratio of about 1 cyclic guanidine group per atom of the backbone.

Hence, according to some embodiments, the polymeric compound is derived from a poly(vicinalamine) or a copolymer thereof. In some embodiments, the polymeric compound comprises more than one type of pendant group (e.g., the compound is a copolymer), for example, more than one species of the cyclic guanidine-containing pendant groups described herein and/or a combination of the cyclic guanidine-containing pendant group described herein and a pendant group which does not comprise a cyclic guanidine. In some embodiments, a weight percentage of the cyclic guanidine groups in the polymeric compound is in a range of from 1 weight percent to 90 weight percents of a

total weight of the polymeric compound, and optionally in a range of from 10 weight percents to 90 weight percents of a total weight of the polymeric compound.

As demonstrated in the Examples section that follows, the present inventors have surprisingly uncovered that the cyclic guanidine-containing polymeric compounds described herein bind phosphate ion to a greater extent than do related polymers, such as amine-containing polymers which are known in the art as strong binders of phosphate ion.

Cyclic guanidines interact more strongly with phosphate anions than N,N'- diethyl amidines [14]. As used herein, the phrase "phosphate ion" encompasses PO 4 " , HPO 4 and

H 2 PO 4 " ions, wherein the relative concentration of the aforementioned ions depends, for example, on the acidity of the environment.

Without being bound by any particular theory, it is believed that the cyclic guanidine groups are particularly suitable for binding phosphate ions due to their positive charge, which is distributed over 3 nitrogen atoms, thereby allowing bidentate and even tridentate binding to the negatively charged phosphate ion.

It is further believed that the alkylene portion of the cyclic guanidine contributes to phosphate binding by not sterically hindering phosphate from binding to the guanidine, as would be expected for various substituents of linear guanidine groups. Phosphate binding may be enhanced in some cases by cross-linking of the polymeric compound, which typically increases cohesiveness and reduces the solubility of the polymeric compound. These effects of cross-linking may also be beneficial for other applications of the polymeric compound.

Hence, according to some embodiments of the invention, the polymeric compound described herein is a cross-linked polymer. The cross-linking may be effected by any mechanism known in the art, for example, by a cross-linking agent.

Suitable cross-linking agents include, without limitation, a diacrylate (e.g., ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, polyethylene glycol diacrylate, bisphenol A diacrylate), a dimethacrylate (e.g., ethylene glycol dimethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate, polyethylene glycol dimethacrylate, bisphenol A dimethacrylate), a diacrylamide (e.g., methylene bisacrylamide, ethylene bisacrylamide, ethylidene bisacrylamide), a

dimethacrylamide (e.g., methylene bisacrylamide, ethylene bismethacrylamide), epichlorohydrin, epibromohydrin, a diisocyanate (e.g., toluene diisocyanate, hexamethylene diisocyanate), divinyl benzene, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1 ,2-dichloroethane, 1,3- dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, and pyromellitic dianhydride. Epichlorohydrin is an exemplary cross-linking agent.

The mechanism of cross-linking and the residue of the cross-linking agent which is obtained in the polymeric compound depend on the type of cross-linking agent used.

Thus, for example, some cross-linking agents (e.g., divinyl benzene, diacrylates) comprise two or more polymerizable units (e.g., vinyl groups) and generate cross-linking in a polymer by being copolymerized with the monomer(s) used to form the polymer.

Other cross-linking agents (e.g., epichlorohydrin, diisocyanates, succinyl dichloride) react with certain groups in a polymer (e.g., nucleophilic groups such as amines). Thus, for example, a polymer cross-linked by epichlorohydrin will characteristically include -CH 2 CH(OH)CH 2 - cross-linking groups linking nucleophilic groups (e.g., amines).

According to some embodiments, the polymeric compound is a molecularly imprinted polymer (MIP). Molecularly imprinted polymers are polymers with a structure suitable for selectively binding a target. Typically, a MIP is generated by forming a polymer with a bound target, followed by release of the target, thereby resulting in "imprints" in the polymer structure.

As discussed hereinabove, the polymeric compounds described herein may be used to binding phosphate.

Hence, according to some embodiments, the MIP is designed capable of selectively binding a phosphate ion.

Enhanced selectivity is an important element en route to achieve increased in- vivo phosphate binding capacity relative to non-MIP polymers such as Renagel® and compounds such as the Symyx's high-amine density polymers. In addition, it can reduce the binding of other pharmaceuticals, which may lead to under-medication of other drugs administered to the treated patient at the same time.

As discussed in the Background section hereinabove, phosphate binding MIPs have been disclosed by Ross et al. [13]. The MIPs described herein are more effective

than the MIPs taught by Ross et al. [13] because of the superior binding of the cyclic guanidines.

In some embodiments, the polymeric compounds described herein are characterized as non-absorbable polymeric compounds. In some embodiments, a cross-linked form of the polymeric compounds described herein is characterized as being non-absorbable.

As used herein, the term "non-absorbable" describes a substance which is non- soluble when subjected to a physiological medium or conditions and/or which is resistant to degradation in a physiological environment (e.g., enzymatic degradation). Non-absorbable polymeric compounds are highly advantageous for applications such as removal of phosphate and other unwanted compound from the body of a subject without entering the blood stream thus reducing potential toxic effects. Another important application is plasmapheresis.

As exemplified hereinbelow, polymeric compounds described herein may be prepared in a simple and convenient manner.

Hence, according to another aspect of embodiments of the invention there are provided processes of preparing a polymeric compound as described herein.

According to one embodiment, the process is effected by reacting a polymer having the polymeric backbone described herein and comprising amino groups dispersed within the polymeric backbone and/or within a plurality of pendant groups attached to the polymeric backbone, with a cyclic guanyl compound. The polymeric compound described herein, comprising a polymeric backbone having a plurality of pendant groups, wherein at least a portion of the pendant groups comprise a cyclic guanidine group, is thereby obtained. Thus, the overall approach comprises reacting amino groups with cyclic guanyl groups to obtain the cyclic guanidine groups.

As used herein, the phrase "cyclic guanyl compound" describes a compound which comprises a cyclic guanyl group. The phrase "cyclic guanyl" describes a group having the formula:

wherein the curved line, Rb, Rd and A, are as defined hereinabove. In some embodiments, the cyclic guanyl compound has the formula:

wherein Rb, Rd and A are as defined hereinabove, and X is a leaving group, such a leaving group suitable for nucleophilic substitution reactions. Exemplary leaving groups include, without limitation, sulfonate and thioalkoxy (e.g., methylthio) groups, such that the cyclic guanyl compound is a cyclic guanyl sulfonate or alkyl cyclic guanyl sulfide (e.g., methyl cyclic guanyl sulfide). Additional suitable leaving groups and cyclic guanyl compounds will be apparent to a skilled artisan.

The cyclic guanyl compound may be reacted with amine groups of any suitable polymer, including polymers, comprising amine groups dispersed within the backbone

(e.g., poly(ethyleneimine)) and polymers comprising amine groups as pendant groups

(e.g., poly(vinylamine)) or within pendant groups (e.g., poly(allylamine), poly(aminoethyl acrylate), poly(4-vinylbenzylamine).

As an example, the reaction of amine groups in poly(vinylamine) to form a cyclic guanidine derivative of poly(vinylamine) is shown in Scheme 1 below:

Scheme 1

Optionally, the amine-containing polymer is a vicinalamine, as defined hereinabove.

In some embodiments, the process is effected by preparing a compound having a polymerizable unit and a cyclic guanidine group as described herein that is attached to the polymerizable unit. The cyclic guanidine group may be attached directly to the polymerizable unit, or indirectly via a linker which links the cyclic guanidine group and the polymerizable unit. The prepared compound is then polymerized to thereby obtain the polymeric backbone described herein having a plurality of pendant groups attached to the polymeric backbone, wherein at least a portion of the pendant groups comprise a cyclic guanidine group. In some embodiments, polymerizing the prepared compound comprises copolymerizing the prepared compound with another compound which comprises a polymerizable unit.

According to some embodiments, any of the processes described herein further comprises reacting the polymeric backbone having a plurality of cyclic guanidine groups attached thereto with a cross-linking agent, as described hereinabove. According to some embodiments, a polymer having a polymeric backbone and comprising amino groups, as described herein, is reacted with a cross-linking agent prior to being reacted with a cyclic guanyl compound, as described hereinabove.

Optionally, the polymeric compound is a MIP, and the process is further effected by reacting the polymeric compound having a plurality of cyclic guanidine groups attached thereto with a cross-linking agent in the presence of a phosphate ion.

As discussed herein, compounds which exhibit a strong affinity towards phosphate, such as exhibited by the polymeric compounds described herein, may be

beneficial in removing phosphate from a subject, for example, by removing phosphate from a gastrointestinal tract of a subject.

Hence, according to another aspect of embodiments of the present invention, there is provided a method or removing a phosphate ion from the gastrointestinal (GI) tract of a subject in need thereof. The method is effected by administering to the subject a therapeutically effective amount of the polymeric compound described herein.

According to another aspect of embodiments of the invention there is provided a method of treating or preventing a medical condition associated with an elevated serum phosphate in a subject. The method is effected by administering to the subject a therapeutically effective amount of the polymeric compound described herein.

Examples of medical condition associated with an elevated serum phosphate include, but are not limited to, hyperphosphatemia, end stage renal disease (ESRD), renal insufficiency, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, overmedication with phosphate salts, and acute tissue destruction during rhabdomyolysis and treatment of malignancies.

The polymeric compounds described herein can be utilized in any of the methods described herein as a part of a pharmaceutical composition, which further comprises a carrier. Thus, according to an aspect of some embodiments of the invention there is provided a pharmaceutical composition that comprises a polymeric compound as described herein and a pharmaceutically acceptable carrier.

As used herein a "pharmaceutical composition" refers to a preparation of a polymeric compound, as described herein, with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

Hereinafter, the term "pharmaceutically acceptable carrier" refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Examples, without limitations, of carriers include: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.

Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.

Examples, without limitation, of excipients include calcium carbonate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Techniques for formulation and administration of drugs may be found in

"Remington's Pharmaceutical Sciences" Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in

"The Pharmacological Basis of Therapeutics", Ch. 1 p.l).

The pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically (including ophtalmically, vaginally, rectally, intranasally).

In one embodiment, the composition is formulated for oral administration. Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.

Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, caplets, capsules or tablets.

Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.

Formulations for parenteral administration may include, but are not limited to, sterile solutions which may also contain buffers, diluents and other suitable additives. Slow release compositions are envisaged for treatment.

The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

Preferably, the polymer or the pharmaceutical composition comprising the polymer is administered orally. The oral form in which the polymer is administered can include powder, tablet, capsule, solution, or emulsion. The effective amount can be administered in a single dose or in a series of doses separated by appropriate time intervals, such as hours.

Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack or a pressurized container (for inhalation). The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a polymeric compound as described herein, formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container, and labeled for treatment of a medical condition, as is detailed herein.

Thus, according to some embodiments of the invention, the pharmaceutical composition is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a condition associated with elevated serum phosphate, as described herein.

According to further embodiments, in each of the methods and compositions presented herein, the polymeric compound can be combined with other active agents which are commonly used to treat the indicated conditions and/or to bind phosphate.

Further, there is provided a use of the polymeric compounds described herein in the manufacture of a medicament. The medicament can be for removing a phosphate ion from the gastrointestinal tract. Additionally or alternatively, the medicament can be for treating or preventing any of a variety of diseases and disorders associated with an elevated serum phosphate. Examples of such diseases and disorders are provided hereinabove. As used herein the term "about" refers to ± 10 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to". The term "consisting essentially of means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges

between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.

MATERIALSAND METHODS

Diethyl ether was obtained from Bio-Lab Ltd. (Israel); Epichlorohydrin was obtained from Fluka;

1,6-hexamethylene diisocyanate was obtained from Fluka;

Hydrochloric acid was obtained from Bio-Lab Ltd. (Israel); Hydrogen peroxide was obtained from Sigma; Methanol was obtained from Bio-Lab Ltd. (Israel); Methyl iodide was obtained from Sigma;

N 5 N' -Ethylene-thiourea was obtained from Sigma; Picric acid was obtained from a government laboratory; Poly(allylamine) was obtained from Sigma;

Sevelamer hydrochloride (Renagel®) was obtained from a hospital pharmacy; Sodium hydroxide was obtained from Bio-Lab Ltd. (Israel);

Sodium molybdate duhydrate was obtained from Sigma; and 4-vinylbenzylamine was prepared as described by Zhu et al. [Chinese Chem. Lett. 19: 355-358 (2008)].

Phosphate stock solution for measuring phosphate binding was prepared with 20 mM of KH 2 PO 4 , 80 mM of NaCl, 100 mM of BES (N,N-Bis(2-hydroxyethyl)-2- aminoethanesulfonic acid). The pH of the solution was adjusted to 6.9 with aqueous

NaOH solution. The stock solution was diluted to the intended phosphate concentration before use.

Melting points were determined using a Fisher- Johns apparatus. 1H-NMR spectra were obtained using a BrukerAMX-250 MHz instrument.

IR spectra were obtained using a Nicolet 510 FT Spectrometer. Elemental analysis was performed at the Microanalysis Laboratory of the Hebrew University Institute of Chemistry.

EXAMPLE l

Synthesis of a cyclic guanidine-containing substance

A synthesis of an exemplary cyclic guanidine-containing monomer and the polymer formed therefrom is depicted in FIG. 1.

Synthesis of an imidazolidine-2-ylidene-(4~vinylbenzyl)-amine (Compound 5), a precursor of a cyclic guanidine-containing polymer:

Preparation of 4,5-Dihydro-lH-imidazolium 2-sulfonate (Compound 4) (according to the procedures described in Kurz & Goebel (1996); Muche & Goebel

(1996); and U.S. Patent No. 4,656,291): A suspension of N 1 N '-ethylene-thiourea

[imidazolidine-2-thione] (2.5 grams, 24.5 mmol) in 30 ml of water was treated with sodium molybdate dihydrate (18 mg, 0.075 mmol, 0.003 equivalents) and cooled to 0 °C in an ice bath. The suspension was maintained at a temperature below 5 °C, and a 15 % hydrogen peroxide solution (16.8 ml, 74 mmol, 3 equivalents) was added dropwise thereto. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to about 20 0 C. After 90 minutes, the reaction solution was diluted with 50 ml of methanol and stored in a refrigerator for about 12 hours. 1.56 grams (42 % yield) of crystallized Compound 4 were obtained. m.p. = 142 °C (decomp.).

1 H NMR (270 MHz, [D 6 ] DMSO): δ = 3.86 (s, 4H, ethylene CH 2 ) 10.38 (br. S, EH,

NH).

Element analysis: Calculated for C 3 H 6 N 2 O 3 S (MW 150.16): C 24.00%, H 4.03%, N

18.66%; found: C 24.10%, H 4.19%, N 18.46%. Preparation of imidazolidine-2-ylidene-(4-vinylbenzyl)-amine (Compound 5)

(isolated as picrate) (based on the teachings of Kurz & Goebel (1996); Muche & Goebel (1996); and U.S. Patent No. 4,656,291, and described in Knorr (2003)): 4- Vinylbenzylamine (0.78 gram, 5.85 mmol) and Compound 4 (0.97 gram, 6.44 mmol, 1.1 equivalent) suspended in 30 ml of methanol, were kept overnight at room temperature. The mixture became clear and was thereafter treated with picric acid (25 ml of a 0.25 N solution in methanol, 6.25 mmol, 1.07 equivalents) and 10 ml of water. The resulting yellow precipitate was recrystallized from water/ethanol. Yield: 1.86 grams (74 %). m.p. = 154° C (decomp.) 1H NMR (500 MHz, [D 6 ] DMSO ): δ = 3.61 (s, 4H, ethylene CH 2 ), 4.36 (d, 3 J H = 6.3 Hz, 2H, Ar-CH 2 -NH + -), 5.25 (dd, 3 J H = 11.0 Hz, 3 J H = 0.7 Hz, IH, cis-CH=CH 2 ), 5.82 (dd, 3 J H = 17.7 Hz, 3 J H = 0.8 Hz, IH, trans-CH=CH 2 ), 6.72 (dd, 3 J H = 17.7 Hz, 3 J H = 10.9 Hz, IH, -CH-CH 2 ), 7.28 (d, 3 J H = 8.2 Hz, 2H, Ar-H), 7.47 (d, 3 J H = 8.1 Hz, 2H, Ar-H), 7.88 (br s, IH, -NH-), 853 (br s, IH, NH-), 8.64 (t, 3 J H = 6.2 Hz, IH, Ar-CH 2 -NH + -). Element analysis: Calculated for C 18 H 18 N 6 O 7 (MW 430.37): C 50.23%, H 4.22%, N 19.53%; found: C 50.33%, H 4.24%, N 19.21%.

Synthesis of poly(imidazolidine-2-ylidene-(4-vinylbenzyl)-amine) as an exemplary polymer with cyclic guanidine pendant groups (Compound 6):

A solution, of Compound 5 (in a solvent such as acetonitrile) is treated with AIBN and degassed with a stream of nitrogen. Polymerization, either by irradiation with a 365 nm lamp, or by heating at 65 0 C, yields the polymer having cycloguanidium pendant groups.

Synthesis of the functional monomer imidazolidine-2-ylidene-(N- methacryloyl-l,2-ethylenediamine) (Compound 7), a precursor of a polymer with pendant cyclic guanidine groups: N-methacryloyl-l,2-ethylenediamine and imidazolidine-2-sulfonic acid

(Compound 4) (10 % molar excess) are suspended in methanol and the solution is stirred overnight at room temperature. The product, Compound 7, is thereafter isolated and characterized.

EXAMPLE 2

Synthesis of 2-methylthio-2-imidazolinium compounds

2-methylthio-2-imidazolinium [2-methylthio-4,5-dihydroimidazolium] salts were prepared as alternatives to 4,5-dihydroimidazole-2-sulfonate (Compound 4).

Synthesis of 2-methylthio-2-imidazolinium iodide (Compound 8): N,N L ethylenethiourea, 10 grams (0.1 mol), was mixed with 16 grams (0.11 mol) of methyl iodide in 150 ml of methanol. The solution was refluxed for 2 hours and then cooled.

150 ml of diethyl ether was then added. The resulting product was collected by filtration and dried in vacuum. The yield of 2-methylthio-2-imidazolinium iodide [or 2- methylthio-4,5-dihydroimidazole hydroiodide] was 22.45 grams. m.p. = 143-144 °C, as compared to 142-144 °C in the literature [Aspinall &

Bianco, J Am. Chem. Soc. 73:602-602 (1951)].

Synthesis of 2-methylthio-2-imidazolinium chloride (Compound 9): 2.4 grams

(0.01 mol) of 2-methylthio-2-imidazolinium iodide, was treated with NaOH solution

(0.02 mol) at room temperature, and the free base was then extracted into ethyl acetate. After evaporation of the solvent, an excess of HCl in diethyl ether was added and the mixture was cooled overnight. 1.25 gram (82 % yield) of the product was collected by filtration and dried in vacuum.

m.p. = 165-167 0 C.

EXAMPLE 3

Synthesis of cross-linked cyclic guanidine-containing polymer

Syntheses of cross-linked cyclic guanidine-containing polymer are depicted in FIG. 2.

In one synthesis (Route A) depicted in FIG. 2, a polymer is cross-linked, after which cyclic guanidine groups are added to the obtained cross-linked polymer.

In another synthesis (Route B) depicted in FIG. 2, cyclic guanidine groups are added to a polymer, after which the resulting cyclic guanidine-containing polymer is cross-linked.

The obtained cross-linked cyclic guanidine-containing polymer is described as Compound 13A when prepared by Route A, and as Compound 13B when prepared by Route B.

Preparation of cross-linked poly(allylamine) (Compound 11): 166 mg of poly(allylamine) (Compound 10) (MW = 65,000 Da) was dissolved in 3 ml of deionized water and 33 mg (0.36 mmoles) of epichlorohydrin was added. The reaction was agitated at room temperature for a period of 24 to 48 hours. The cross-linked poly(allylamine) (Compound 11) was isolated after dialysis against water and lyophilization (See FIG. 2). Similar procedures were performed using various amounts of epichlorohydrin

(between 5 % and 40 % w/w) and/or with 17,000 Da poly(allylamine).

Poly(allylamine) was also crosslinked with 1,6-hexamethylene diisocyanate. The resulting polymer was less gel-like than the cross-linked polymer obtained with epichlorohydrin. Preparation of cycloguanidine derivative of cross-linked poly(allylamine)

(Compound 13A): 180 mg (2.9 mmol) of Compound 11 was suspended in 3 ml methanol and mixed with 218 mg (1.5 mmol) of Compound 4 (4,5-dihydroimidazole- sulfonate). The obtained suspension was stirred at room temperature for 24 hours. The methanol was then evaporated and the cycloguanidinylated polymer (Compound 13A) was suspended in 4 ml of de- ionized water, and purified by dialysis.

In an alternative procedure, Compound 8 (2-methylthio-2-imidazolinium iodide) was used instead of Compound 4.

1 gram of Compound 11 and 130 mg of Compound 8 were mixed in 10 ml of methanol. The reaction mixture was heated and stirred overnight. After cooling, the methanol was evaporated. The residue was transferred to a centrifuge tube with 15 ml of methanol, and after 5 minutes of centrifugation at 3000 rpm, the solvent was discarded. This procedure was repeated three times. The obtained polymer (Compound 13A) was dried by lyophilization to yield 1.097 grams of a yellowish powder.

The product was characterized by IR spectroscopy. IR bands at 1665 cm "1 and 1596 cm "1 , characteristic of cycloguanidine groups, were observed.

In another alternative procedure, Compound 9 (2-methylthio-2-imidazolinium chloride) was used instead of Compound 4 or Compound 8.

The IR spectrum of the product prepared using Compound 9 had bands at 1670 cm "1 and 1602 cm "1 , characteristic of cycloguanidine groups.

Preparation of cycloguanidine derivative of non-cross-linked poly(allylamine)

(Compound 12): 166 mg of poly(allylamine) (Compound 10) (MW = 65,000 Da) was suspended in 3 ml methanol and treated with Compound 4, as described hereinabove for guanidinylation of cross-linked poly(allylamine) (Compound 11). Evaporation of the solvent afforded Compound 12 (See FIG. 2).

Preparation of cross-linked cycloguanidinylated poly(allylamine) (Compound 13B): 166 mg of Compound 12 was dissolved in water and the pH was adjusted to 10 with aqueous NaOH. 33 mg (0.36 mmol) of epichlorohydrin (20 % w/w) was added. The mixture was agitated for 48 hours, yielding Compound 13B (See FIG. 2).

Similar procedures were performed using various amounts of epichlorohydrin between 5 % and 40 % w/w.

EXAMPLE 4 Synthesis of cyclic guanidine-containing polymer using sevelamer hydrochloride

A cyclic guanidine-containing polymer was prepared as described in Example 3, using commercially available sevelamer hydrochloride (epichlorohydrin-cross-linked poly(allylamine) hydrochloride) as Compound 11, as depicted in FIG. 3.

A Renagel® sevelamer hydrochloride tablet was ground using a mortar and pestle. 200 mg of the ground tablet were suspended in 10 ml methanol. 110 mg of 2-

methylthio-2-imidazolinium chloride (Compound 9) was added to the stirred suspension which was heated overnight. The polymer was shaken five times with hot methanol and centrifuged after each shake, and the methanol was then decanted. Finally, the solvent was removed to give the dry polymer (Compound 13 A). Similarly, Renagel® sevelamer hydrochloride was converted to the cycloguanidine derivative using Compound 4 (4,5-dihydroimidazole-2-sulfonate).

The structure of Renagel® sevelamer hydrochloride depicted in FIG. 3 is taken from Mazzeo et al., J. Pharm. Biomed Anal. 1999, 19:911-915. a and b describe the proportion of primary amino groups (a+b=9); c describes the proportion of cross-linked groups (c=l); n is the fraction of protonated amines, and equals about 0.4; and m is a large number, indicating an extended polymer network.

EXAMPLE S

Synthesis of imprinted crosslinked insoluble polymer with phosphate-binding cyclic guanidine groups

Phosphate anions (10 times excess) are added to a solution of the functional monomer Compound 5, prepared as described herein, in acetonitrile, and the reaction mixture is stirred for an hour. Freshly distilled cross linker (ethylene glycol dimethacrylate, 95% by weight) and AIBN (azo-isobutyronitrile, initiator, 1% by weight) are thereafter added and the obtained mixture is placed in an ampoule. After three freeze-thaw cycles, the ampoule is heated at 70 0 C overnight. The resulting polymer is crushed and washed with acetonitrile, followed by MeOH. The phosphate ions are removed by warming the polymer in a Soxhlet apparatus for 24 hours to reflux, using aqueous methanol and, finally, the polymer is dried at 100 0 C for 24 hours.

EXAMPLE 6

Preparation of 6-membered cyclic guanidine-containing substances In a variation of the syntheses described hereinabove, N,N'-trimethylene- thiourea (Compound 14) is used instead of N,N' -ethylene-thiourea. Compound 14 is converted to either Compound 15 or Compound 16, depicted hereinbelow, using the procedures described hereinabove for preparing Compounds 4 and 9 from N 5 N'- ethylene-thiourea.

Compound 15 or Compound 16 is then reacted with Compound 11 (optionally sevelamer hydrochloride), as described hereinabove for Compounds 4, 8 and 9 to the corresponding polymers containing 6-membered cycloguanidines.

16

EXAMPLE 7

Comparative in-vitro evaluation of the phosphate binding capacities of the cyclic guanidine-containing polymers

The phosphate binding capacities of the cycloguanidine-containing polymers (Compound 13A) prepared as described in Examples 3 and 4 were compared to those of the cross-linked poly(allylamine) (Compound 11) from which they were derived. 10-20 mg of polymer was mixed under gentle agitation with 10-15 ml of 20 mM phosphate ion solution buffered at pH 6.9. The solution can be referred to as a non-interfering buffer as it contains no other competing solutes that compete with the phosphate ions for binding to the polymer resin. After equilibration, the solution was filtered using a polytetrafluoroethylene (PTFE) syringe filter (25 mm, 0.45 μm), diluted 10-fold and analyzed for residual phosphate concentration using the Fiske-Subbarow procedure and by Ion Chromatography.

The Fiske-Subbarow procedure was performed using a molybdate solution prepared from 1.25 grams of ammonium molybdate, 10 ml water, and 25 ml of sulfuric acid (10 N), followed by dilution with water to a volume of 50 ml; and a freshly prepared 0.25 % aminonaphtolsulfonic acid solution, prepared from 10 mg of 4-amino-

3-hydroxy-l-naphtalenesulfonic acid, 3.9 ml of 15 % sodium bisulfite aqueous solution, and 0.1 ml of 20 % sodium sulfite aqueous solution.

Calibration curves were constructed using a UVWIN 5.0 instrument with solutions having the following phosphate concentrations: 5 mM, 4 mM, 2 mM, 1 mM. 0.5 mM, and 0.25 mM.

Ion Chromatography was performed in the Analytical Laboratory of the Hebrew University Faculty of Agriculture.

The binding capacity is expressed in mmol phosphate per gram of polymer.

Compound 13A prepared as described in Example 3 exhibited a 32 % greater uptake of phosphate than did Compound 11 prepared as described in Example 3 under identical conditions. Specifically, phosphate uptake by Compound 11 was 1.00 mmol/gram of polymer, whereas phosphate uptake by Compound 13A was 1.32 mmol/gram.

Compound 13A prepared as described in Example 4 exhibited a 25 % greater uptake of phosphate than did Renagel® (Compound 11 in Example 4) under identical conditions.

These results indicate that cycloguanidine derivatives of poly(allylamine) exhibit superior phosphate binding than does the poly(allylamine) from which they are derived.

EXAMPLE 8 Comparative in-vitro evaluation of the phosphate binding capacities of the cyclic guanidine-containing polymers using a digestion model

This procedure is designed to mimic the conditions of use of a phosphate binding polymer in a GI tract and measure the binding characteristics of the polymer for phosphate (target solute) in the presence of other metabolites (competing solutes). A liquid meal is prepared and the polymer is added to the meal composition and the meal is artificially digested in the presence of pepsin and pancreatic juice. The sequence of addition of enzymes and the pH profile are controlled so that the digestion process is simulated down to the jejunum level. An aliquot of the digested meal mimic is centrifuged and the supernatant assayed for phosphate. The phosphate binding assay is like the one described above with non-interfering buffer, except that liquid of the meal

digest mimic is used. The binding capacity in the meal digest is calculated as indicated above.

EXAMPLE 9 Comparative in-vitro evaluation of phosphate-binding capacities of cyclic guanidine- containing polymers and non-substituted guanidine-containing polymers

Preparation of polymers containing cyclic guanidine groups and non-substituted guanidine groups (-NH-CC=NH)NH 2 ) is depicted schematically in FIG. 4.

The monomer Compound 17 is synthesized as described in Prabhakaran and Sanjayan [Tetrahedron Letters, 48: 1725-1727 (2007)] using the reagent NJψN" -tά-Boo- guanidine (TBG), followed by hydrolysis. The monomer Compound 18 is prepared in the same way as Compound 5, Compound 7 and other compounds described herein, using Compound 4 (4,5-dihydroimidazole-2-sulfonate). Polymerization of Compounds 17 and 18 to give the corresponding cross-linked polymers (Compounds 19 and 20, respectively) is achieved by carrying out the polymerization in water containing the monomer along with an initiator, 2,2'-azobis(amidinopropane) dihydrochloride (Waco Chemicals), and the crosslinker bis, N,N'-methylene-bisacrylamide.

The obtained polymers (Compounds 19 and 20), are washed to remove reagents and lyophilized. The relative phosphate binding capacity is then measured as described in Examples 7 and 8.

Under identical conditions, the cycloguanidine polymer Compound 20 is expected to bind at least about 15 % more phosphate than the non-substituted guanidine polymer Compound 19 in view of, for example, the results with similar substances presented herein. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all

such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

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